Throughout the lives of multi-cellular organisms, cells of all types undergo periods of division, differentiation, and death. These processes are essential for normal development and tissue homeostasis, and over time, the dysregulation of mechanisms that either increase or decrease cell numbers leads to organismal aging and disease. This proposal investigates the relationship between two of the most important mechanisms that control cellular homeostasis: programmed cell death (apoptosis) and programmed irreversible cell cycle arrest (senescence). This research proposal hypothesizes that tight regulation of apoptosis is achieved in part by a checkpoint mechanism that evaluates the integrity of the apoptotic machinery. When this integrity ig lost, or when apoptosis signals are detected in inappropriate contexts, the checkpoint is activated and triggers premature cellular senescence as a pre-emptive, alternative program to thwart the deleterious consequences of dysregulated apoptosis. Caspases, a family of cysteine proteases, are the central molecular executors of apoptosis. Preliminary work suggests that in somatic cells, exogenous expression of caspase proteins is detected as an aberration in the apoptotic machinery an prompts the premature activation of the cellular senescence program. This suggests that in normal cells, endogenous caspases have an important and as yet unappreciated function, which when perturbed, leads to senescence. This proposal aims to study at the molecular level this unexplored area in apoptosis regulation and its relation to cellular senescence. The long- term goal is to further our understanding of aging-related disease processes and to identify novel targets for pharmacological intervention. Specifically, the project aims to: (1) Carry out a functional analysis of the caspase activity required for senescence regulation. (2) Characterize the proteins and signaling pathways operating in caspase- regulated senescence. (3) Identify and characterize novel proteins required for caspase-regulated senescence. The research will be conducted in the department of Cell Biology at Harvard Medical School, under the mentorship of Dr. Junying Yuan. Dr, Yuan is a recognized leader in the field of apoptosis, with an exceptional record for fostering the career development of physician- scientists. Dr. Yuan and the department are fully committed to the applicant's development into a fully independent clinician-scientist in the medically important fields of a o tosis and cellular senescence.